A Study to Compare Tenofovir Versus Hepsera (Adefovir) for the Treatment of HBeAg Negative Chronic Hepatitis B

This study is ongoing, but not recruiting participants.

Sponsor:

Information provided by:

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00117676

First received: June 30, 2005

Last updated: January 5, 2011

Last verified: January 2011

History of Changes

Results First Received: February 11, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Chronic Hepatitis B
Interventions:	Drug: Tenofovir DF (TDF) 300 mg Drug: Double-blind adefovir dipivoxil (ADV) 10 mg (switch to open-label TDF 300 mg post Week 48)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There were 79 enrolling sites in 15 countries. The first participant was screened on 07 June 2005, and the last participant was randomized on 15 May 2006. The last participant observation (LPO) for the primary endpoint analysis (Week 48) was 13 April 2007. The LPO for the Week 96 analysis was 06 May 2008.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Seven of the 382 participants who were randomized discontinued prior to the first dose of study drug either due to screening failure (after erroneously being randomized via interactive voice response system) or withdrawal of consent. The screening process involved a liver biopsy.

Reporting Groups

	Description
TDF 300 mg QD	Double-blind TDF 300 mg once daily for 48 weeks followed by OL TDF for an additional 336 weeks.
ADV 10 mg QD	Double-blind ADV 10 mg once daily for 48 weeks then switch to OL TDF 300 mg once daily for an additional 336 weeks.

Participant Flow for 2 periods

Period 1: Double-blind Period Through Week 48

	TDF 300 mg QD	ADV 10 mg QD
STARTED	250 ^[1]	125 ^[1]
COMPLETED	234 ^[2]	113 ^[2]
NOT COMPLETED	16	12
Lost to Follow-up	1	0
Safety, Tolerability, or Efficacy	5	2
Withdrawal by Subject	0	1
Protocol Violation	0	1
No end-of-blinded-treatment liver biopsy	6	5
Unusable end-of-blinded-treatment biopsy	4	3

[1]	Randomized-and-treated participants
[2]	Completed through Week 48 with usable end-of-blinded treatment liver biopsy result

Period 2: Open-label TDF Period Through Week 96

	TDF 300 mg QD	ADV 10 mg QD
STARTED	235 ^[1]	112 ^[2]
COMPLETED	225 ^[3]	110 ^[3]
NOT COMPLETED	10	2
Lost to Follow-up	3	0
Safety, Tolerability, or Efficacy	2	1
Withdrawal by Subject	5	1

[1]	Entered the OL TDF phase. One participant entered OL without a usable Week 48 biopsy specimen.
[2]	Entered the OL TDF phase
[3]	Completed through Week 96

Baseline Characteristics

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Reporting Groups

	Description
TDF 300 mg QD	Double-blind TDF 300 mg once daily for 48 weeks followed by OL TDF for an additional 336 weeks.
ADV 10 mg QD	Double-blind ADV 10 mg once daily for 48 weeks then switch to OL TDF 300 mg once daily for an additional 336 weeks.
Total	Total of all reporting groups

Baseline Measures

	TDF 300 mg QD	ADV 10 mg QD	Total
Number of Participants [units: participants]	250	125	375
Age [units: Participants]
<=18 years	0	1	1
Between 18 and 65 years	247	123	370
>=65 years	3	1	4
Age [units: years] Mean ± Standard Deviation	44 ± 10.6	43 ± 10.0	44 ± 10.4
Gender [units: participants]
Female	57	28	85
Male	193	97	290
Race/Ethnicity, Customized ^[1] [units: Participants]
American Indian or Alaska Native	0	0	0
Asian	63	30	93
Native Hawaiian or Other Pacific Islander	7	2	9
Black or African American	8	4	12
White	161	81	242
More than one race	0	0	0
Unknown or Not Reported	11	8	19
Region of Enrollment [units: participants]
United States	25	11	36
Greece	19	9	28
Spain	15	6	21
Turkey	11	3	14
Italy	6	0	6
United Kingdom	5	2	7
France	13	5	18
Czech Republic	7	5	12
Canada	29	18	47
Poland	13	11	24
Australia	14	8	22
Bulgaria	49	23	72
Germany	19	11	30
Netherlands	1	1	2
New Zealand	24	12	36
Baseline Alanine Aminotransferase (ALT) Above the Upper Limit of the Normal (ULN) Range ^[1] [units: Participants]
Yes	236	118	354
No	14	7	21
Prior Lamivudine or Emtricitabine Experience ^[1] [units: Participants]
Yes	43	23	66
No	207	102	309
Baseline Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) ^[1] [units: Log10 copies/mL] Mean ± Standard Deviation	6.86 ± 1.308	6.98 ± 1.266	6.90 ± 1.294
Baseline Knodell Necroinflammatory Score ^[2] [units: Units on a scale] Mean ± Standard Deviation	7.8 ± 2.45	7.8 ± 2.20	7.8 ± 2.37

[1]	Randomized-and-treated analysis set
[2]	Randomized-and-treated analysis set. Based on Knodell numerical scoring of liver biopsy specimens. This scale consists of 5 domains (Periportal with or without Bridging Necrosis [scored numerically from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [scored best to worst 0 to 4]; Portal Inflammation [also scored best to worst 0 to 4]; and Fibrosis [also scored best to worst 0 to 4]). The necroinflammatory score is the combined score for necrosis and inflammation, excluding the fibrosis score. Scores may range from 0 (best) to 14 (worst).

[1]

Randomized-and-treated analysis set

[2]

Randomized-and-treated analysis set. Based on Knodell numerical scoring of liver biopsy specimens. This scale consists of 5 domains (Periportal with or without Bridging Necrosis [scored numerically from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [scored best to worst 0 to 4]; Portal Inflammation [also scored best to worst 0 to 4]; and Fibrosis [also scored best to worst 0 to 4]). The necroinflammatory score is the combined score for necrosis and inflammation, excluding the fibrosis score. Scores may range from 0 (best) to 14 (worst).

Outcome Measures

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1. Primary:

Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48 [ Time Frame: 48 weeks ]

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2. Secondary:

Percentage of Participants With HBV DNA <400 Copies/mL at Week 48 [ Time Frame: Week 48 ]

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3. Secondary:

Percentage of Participants With HBV DNA <400 Copies/mL at Week 96 [ Time Frame: Week 96 ]

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Measure Type	Secondary
Measure Title	Percentage of Participants With HBV DNA <400 Copies/mL at Week 96
Measure Description	No text entered.
Time Frame	Week 96
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis set included all participants who received at least one dose of open-label TDF (Open-label Extension [OLE] analysis set). Participants with missing values at Week 96 or who added emtricitabine to their open-label TDF regimen were considered failures.

Reporting Groups

	Description
TDF-TDF	Double-blind TDF 300 mg once daily for 48 weeks followed by open-label TDF 300 mg once daily for an additional 336 weeks (TDF-TDF)
ADV-TDF	Double-blind ADV 10 mg once daily for 48 weeks then switch to open-label TDF 300 mg once daily for an additional 336 weeks (ADV-TDF)

Measured Values

	TDF-TDF	ADV-TDF
Number of Participants Analyzed [units: participants]	235	112
Percentage of Participants With HBV DNA <400 Copies/mL at Week 96 [units: Percentage of participants]
Yes	89	96
No	2	2
Missing	9	3

Statistical Analysis 1 for Percentage of Participants With HBV DNA <400 Copies/mL at Week 96

Groups ^[1]	All groups
Non-Inferiority/Equivalence Test ^[2]	Yes
Method ^[3]	Z-test
P Value ^[4]	0.022
Difference in proportions ^[5]	-6.4
Standard Error of the mean	± 2.8
95% Confidence Interval	( -11.8 to -0.9 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	With a sample size of 200 subjects in the tenofovir DF group and 100 subjects in the adefovir dipivoxil group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the tenofovir DF treatment was inferior to the adefovir dipivoxil treatment (difference in proportions was less than 0.100) in favor of the alternative hypothesis that the tenofovir DF treatment was not inferior.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference is zero. Two-sided 95% confidence intervals, stratified by baseline ALT (baseline ALT </= 2 x ULN, >2 x ULN), were used to evaluate treatment arm differences.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary:

Percentage of Participants With Histological Response at Week 48 [ Time Frame: Week 48 ]

Show Outcome Measure 4

5. Secondary:

Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 [ Time Frame: Week 48 ]

Show Outcome Measure 5

6. Secondary:

Percentage of Participants With ALT Normalization at Week 96 [ Time Frame: Week 96 ]

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7. Secondary:

Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48 [ Time Frame: Week 48 ]

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8. Secondary:

Percentage of Participants With HBsAg Loss or Seroconversion at Week 96 [ Time Frame: Week 96 ]

Show Outcome Measure 8

9. Secondary:

Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance) [ Time Frame: Week 48 ]

Show Outcome Measure 9

10. Secondary:

Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance) [ Time Frame: Week 96 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Institution and investigator may publish or present the results of the trial generated there with prior written consent of Gilead; or 2 years after the trial has ended at all institutions. Proposed publications/target venue must go to Gilead 30 days (manuscripts) or 15 days (abstracts/presentations) prior. Any Gilead confidential information in the document(s) must be deleted, or if requested publication delayed for up to 45 days to permit Gilead to obtain intellectual property protection.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Jane Anderson, Associate Director Clinical Research
Organization: Gilead Sciences
phone: 919-294-7160
e-mail: Jane.anderson@gilead.com

No publications provided by Gilead Sciences

Publications automatically indexed to this study:

Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011 Jan;140(1):132-43. Epub 2010 Oct 16.

Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442-55.

Responsible Party:	Jeffrey D. Bornstein, MD/ Sr. Director, Clinical Research, Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00117676 History of Changes
Other Study ID Numbers:	GS-US-174-0102
Study First Received:	June 30, 2005
Results First Received:	February 11, 2010
Last Updated:	January 5, 2011
Health Authority:	United States: Food and Drug Administration

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